Alpha1-proteinase inhibitor (abbreviated herein as A1PI; also known as alpha-1 protease inhibitor, alpha-1 PI, A1PI, α-1 PI, α2PI, alpha-1 trypsin inhibitor, alpha-1 antitrypsin, alpha1AT, A1A, and A1AT, AAT, inter alia), is the major serine protease inhibitor (serpin) in humans. A1PI is expressed as a 418 amino acid protein with residues 1-24 being a signal peptide. The mature protein, consisting of residues 25-418, is a single chain glycoprotein having a molecular weight of about 51 kD. See FIG. 1. While A1PI does not contain any disulfide bonds, the protein is highly structured, with 80% of the amino acids residing in eight well-defined α-helices or three large β-sheets. Three asparagine-linked carbohydrates are found on Asn 70, Asn 107, and Asn 271 (numbered as in the full-length protein). This gives rise to multiple A1PI isoforms, having isoelectric points in the range of 4.0 to 5.0. The glycan monosaccharides include N-acetylglucosamine, mannose, galactose, fucose, and sialic acid.
Normal plasma concentrations of A1PI range from 1.3 to 3.5 mg/mL. A1PI functions by protecting cells from proteases involved in clotting and inflammation. A1PI inhibits trypsin, chymotrypsin, and various forms of elastases, skin collagenase, renin, urokinase, and proteases of polymorphonuclear lymphocytes, among others. A1PI serves as a pseudo-substrate for these proteases, which attack the reactive center loop of the A1PI molecule (residues Gly 368-Lys 392) by cleaving the bond between Met 358-Ser 359 residues forming an A1PI-protease complex. This complex is rapidly removed from the blood circulation.
One of the endogenous roles of A1PI is to regulate the activity of neutrophil elastase, which breaks down foreign proteins and injures native tissue present in the lung. In the absence of sufficient quantities of A1PI, the elastase breaks down lung tissue, which over time results in chronic lung tissue damage and emphysema.
The A1PI protein is an acute phase reactant protein and, as such, its synthesis is amplified during episodes of inflammation or stress, which particularly occurs in exacerbation periods. A1PI deficient patients risk severe lung damage during exacerbation periods, due to the inability to mount an effective acute phase A1PI elevation. Relative deficiencies of A1PI may also occur in normal individuals during acute exacerbation periods, resulting in the excess of neutrophil elastase, which leads to the destruction of lung tissue.
Intravenous A1PI has been use as a treatment for alpha1-antitrypsin deficiency (AATD; i.e., A1PI deficiency), a congenital disease. The consequence of the low levels of A1PI in the lower respiratory tract epithelial lining fluid of individuals with AATD is an insufficient antineutrophil elastase protective screen of the lung, such that a neutrophil elastase is able to act unimpeded to attack and destroy alveolar structures. The resulting lung damage is greatly accelerated by cigarette smoking and is irreversible.
In addition, inhaled A1PI has been proposed as an acute therapy to shorten the severity and duration of established acute pulmonary exacerbations. See U.S. Pat. Nos. 7,879,800 and 7,973,005. However, established pulmonary exacerbations can be difficult to eradicate using A1PI. In addition, repetitive exacerbations damage lung tissue and can progressively reduce a subject's FEV1. The administration of A1PI at the initiation of inflammation is believed to be more efficacious than waiting for additional exacerbation symptoms to develop, which can lag behind the onset of inflammation by hours to days. Improved therapy that delays the onset or diminishes the progression of pulmonary exacerbations a priori is desirable.